US6323230B1ExpiredUtility
Use of nitrogen heterocyclic aromatic derivatives in the topical treatment of the epithelial tissues diseases
Est. expiryJun 5, 2017(expired)· nominal 20-yr term from priority
Inventors:Carla Rossi
A61P 43/00A61P 1/00C07D 495/04C07D 249/08A61P 17/00A61P 17/06C07D 487/04C07D 471/04
41
PatentIndex Score
9
Cited by
11
References
29
Claims
Abstract
Derivatives of general chemical formula L(I) and (IV) are used in the topical treatment of diseases of the epithelial tissues, like psoriasis (epidermis) and ulcerative colitis L(lower intestine). These compounds display a high efficacy when administered for example by epicuaneous route in the case of dermatological illnesses like psoriasis, atopic dermatitis and other similar affections, or when administered by oral or rectal route in the case of diseases of the epithelia of the lower intestine like the ulcerative colitis and Crohn's disease.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method for the topical treatment of epithelial tissue diseases which comprises administering to a subject in need thereof an effective amount of an heterocyclic aromatic compound having the following formulae (I) or (IV):
wherein:
X═Y═N;
R is selected from
hydrogen;
COR 8 wherein R 8 is C 1 -C 10 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl, phenyl optionally substituted by 1 to 3 substituents, benzyl, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, phenylamino optionally substituted by 1 to 3 substituents, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, benzyloxy, each optional substituent being independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoro-methyl, CN, nitro, amino, di-(C 1 -C 4 -alkyl)amino, acyl-aminoC 2 -C 4 and methylenedioxy; and
SO 2 R 12 wherein R 12 is selected from C 1 -C 4 alkyl, phenyl, (C 1 -C 4 alkyl)phenyl, (C 1 -C 4 alkoxy)phenyl, and acetyl-phenyl;
R 1 has the following formula:
wherein
R 3 and R 4 are independently selected from:
hydrogen;
halogen;
C 1 -C 10 alkyl or alkoxyl C 1 -C 10 ;
allyloxy, propargyloxy;
trifluoro-methyl;
phenyl; and
di-methylamino,
or
R 3 and R 4 together form a methylenedioxy group;
R 2 has the following structure:
wherein
R 6 is selected from:
hydrogen,
halogen,
C 1 -C 10 alkyl and alkoxyl C 1 -C 10 ;
R 10 is selected from:
hydrogen; and
methyl;
R 11 is selected from:
hydrogen;
C 1 -C 4 alkyl; and
formyl;
OR 5 wherein R 5 is selected from hydrogen, and C 1 -C 4 alkyl, or R 5 is selected from:
wherein Z═OR, with R 7 is a saturated or non-saturated, linear or branched C 1 -C 20 aliphatic hydrocarbon, or R 7 has the following formula:
wherein R, R 6 , R 1 , X and Y are defined as above or Z is selected from C 1 -C 20 linear or branched alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl, phenyl optionally substituted by 1 to 3 substituents, benzyl, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, phenyl-amino optionally substituted by 1 to 3 substituents, C 1 -C 4 halo-alkyl, C 1 -C 4 alkoxy, benzyloxy, each optional substituent being independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoro-methyl, CN, nitro, amino, of (C 1 -C 4 alkyl)amino, acyl-aminoC 2 -C 4 and methylenedioxy;
or Z is NHR 9 wherein R 9 is an alkenyl chain C 1 -C 20 , linear or branched;
provided that R 1 and R 2 are not located on two adjacent atoms of the heterocyclic aromatic ring; Formula (IV):
wherein
R 15 and R 16 are selected from:
hydrogen;
halogen;
C 1 -C 4 alkyl or alkoxyl C 1 -C 4 ;
C 3 -C 5 alkyl or alkoxyl C 1 -C 5 ;
cycloalkyloxyl C 3 -C 6 ,
benzyloxy; and
halogen;
or
R 15 and R 16 represent together a methylenedioxy group;
R 13 R 14 are selected from:
hydrogen;
halogen; and
C 1 -C 4 alkoxyl;
A is —CH 2 —CH═CH—, —CH 2 CH 2 —, (CH 2 ) 3 , or —CH 2 S—;
B is C or N;
D is C, or N;
or B and D together are equal to C═C;
E is N, C, CO, NH, CH, NR 17 , or CR 17 wherein R 17 is a linear C 1 -C 4 alkyl;
F is CH, or N;
W is selected from N, NH, CH, NR 17 , CR 17 , and CR 16 , wherein CR 17 is defined as above and R 18 is carboxy, carbo(C 1 -C 4 alkyl), carbamyl, mono or di-(C 1 -C 4 alkyl)carbamyl, hydroxymethyl; provided that the ring formed by W-F-E-D-B is a triazole or a tetrazole.
2. The method according to claim 1 wherein, in formula (IV), R 13 and R 14 are both hydrogen; A is selected from —CH 2 —, —CH═CH— and —CH 2 —CH 2 —; D is N; B is C; W is N, R 15 is hydrogen, and R 16 is C 1 -C 4 alkoxy or phenyl.
3. The method according to claim 1 wherein the epithelial tissue diseases are psoriasis or atopic dermatitis.
4. The method according to claim 1 wherein the epithelial tissue diseases are ulcerative colitis or Crohn's disease.
5. The method according to claim 1 wherein the compound of formula (IV) has the following chemical structure:
6. The method according to claim 1 wherein the compound of formula (IV) has the following chemical structure:
7. The method according to claim 1 wherein the compound of formula (IV) has the following chemical structure:
8. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
9. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
10. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
11. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
12. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
13. The method according to claim 1 wherein the compound of formula (I) has the following chemical structure:
14. The method according to claim 1 wherein the administration is by the epicutaneous route.
15. The method according to claim 1 wherein the administration is by the oral route.
16. The method according to claim 1 wherein the administration is by the rectal route.
17. The method according to claim 1 wherein the compound of formula (I) or (IV) is administered in combination with another drug to treat epithelial tissues.
18. A pharmaceutical topical, epicutaneous or transdermal composition which comprises together with a carrier or diluent a compound of claim 1 as active ingredient.
19. The pharmaceutical composition according to claim 18 formulated using lipid vehicles.
20. The pharmaceutical composition according to claim 19 wherein said lipid vehicles are selected from sesame oil, corn oil, peanut oil, cotton seed oil, and ethyl oleate.
21. The pharmaceutical composition according to claim 18 which further comprises an anti-microbial agent.
22. The pharmaceutical composition according to claim 18 which further comprises an anti-oxidant.
23. The pharmaceutical composition according to claim 18 which comprises 0.01% to 0.5% (w/w) of active ingredient.
24. The pharmaceutical composition according to claim 18 which is a cream containing in 100 g:
100.0
mg
Crodabase PC-M
10.24
g
Cetylic Alcohol
5.37
g
semi-synthetic liquid triglycerides
8.51
g
dymeticone
1.70
g
paraseptics
0.15
g
sweet almond oil
2.80
g
stearine (stearic acid)
0.97
g
propylene glycol
4.26
g
tetra-sodic EDTA
0.14
g
carbomer (carboxy-vinylpolymer)
0.16
g
triethanolamine 99%
0.10
g
purified water (to 100 g)
65.5
g.
25. A nitrogen heterocyclic aromatic compound having the following formula (I):
wherein X═Y═N;
R is selected from:
hydrogen; and
COR 8 wherein R 8 is a saturated or non-saturated C 1 -C 10 aliphatic hydrocarbon;
R 1 has the following structure:
wherein:
R 3 and R 4 are each independently selected from hydrogen;
halogen;
CC 1 -C 10 alkyl and alkoxyl C 1 -C 10 ;
or R 3 and R 4 together form a methylenedioxy group;
R 2 has the following structure:
wherein
R 6 is selected from:
hydrogen;
halogen;
C 1 -C 10 alkyl and C 1 -C 20 alkoxyl;
R 10 is hydrogen,
R 11 is OR 5 , wherein R 5 is selected from C 1 -C 20 saturated or non-saturated, linear or branched aliphatic hydrocarbon, or R 5 is selected from:
wherein Z═OR, with R 7 selected from a saturated or non-saturated, linear or branched C 1 -C 20 aliphatic hydrocarbon, or R 7 has the following formula (XII):
wherein R, R 1 , R 6 , X and Y are defined as above or Z is NHR, wherein R 9 is a C 1 -C 20 linear or branched alkyl chain;
provided that R 1 and R 2 are not located on two adjacent atoms of the heterocyclic aromatic ring.
26. The nitrogen heterocyclic aromatic compound according to claim 25 having the following formula:
27. The nitrogen heterocyclic aromatic compound according to claim 25 having the following formula:
28. A pharmaceutical composition which comprises together with a carrier or a diluent a compound of claim 25 as active ingredient.
29. A pharmaceutical composition according to claim 28 for the topical treatment of psoriasis, atopic dermatitis, ulcerative colitis or Crohn's disease.Join the waitlist — get patent alerts
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